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The Lancet. Haematology Dec 2022Blinatumomab is effective in relapsed or refractory B-cell acute lymphocytic leukaemia and results in high rates of minimal residual disease negativity. We aimed to...
Hyper-CVAD and sequential blinatumomab for newly diagnosed Philadelphia chromosome-negative B-cell acute lymphocytic leukaemia: a single-arm, single-centre, phase 2 trial.
BACKGROUND
Blinatumomab is effective in relapsed or refractory B-cell acute lymphocytic leukaemia and results in high rates of minimal residual disease negativity. We aimed to establish whether the incorporation of blinatumomab into front-line therapy for acute lymphocytic leukaemia could improve outcomes.
METHODS
We conducted a single-arm, phase 2 trial at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients aged 14 years or older with confirmed, newly diagnosed Philadelphia chromosome (Ph)-negative B-cell acute lymphocytic leukaemia were eligible, including patients who had received up to one course of chemotherapy before enrolment. Patients received four cycles of intensive chemotherapy (hyper-CVAD [hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone] alternating with high-dose methotrexate and cytarabine), followed by four cycles of blinatumomab consolidation (up to 28 μg/day by continuous intravenous infusion for 28 days, given every 42 days). Maintenance consisted of 15 cycles of alternating blocks of three cycles of POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone) chemotherapy and one of blinatumomab. The primary endpoint was relapse-free survival evaluated in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT02877303, and is still enrolling patients.
FINDINGS
Between Nov 14, 2016, and Aug 27, 2020, 38 patients with newly diagnosed B-cell acute lymphocytic leukaemia were treated (median age 37 years [IQR 29-45]; 26 [68%] male; 21 [55%] White, non-Hispanic). With a median follow-up of 37 months (IQR 28-49), estimated 3-year relapse-free survival was 73% (95% CI 56-85). No patients relapsed more than 2 years after the start of therapy. One (3%) patient developed transient grade 3 cytokine release syndrome, and four (11%) patients had a grade 3 blinatumomab-related neurological event. The most common non-haematological grade 3-4 adverse events were infections, which occurred in 14 (37%) of 38 patients during induction and in 27 (71%) of 38 patients during consolidation chemotherapy cycles. One (3%) patient discontinued therapy because of treatment-related neurotoxicity. There were two deaths-one due to infection and one due to respiratory failure-which were not considered treatment-related.
INTERPRETATION
Front-line sequential chemotherapy with blinatumomab resulted in encouraging long-term survival. Future randomised studies should evaluate the routine incorporation of blinatumomab in the treatment of patients with Ph-negative B-cell acute lymphocytic leukaemia.
FUNDING
Amgen.
Topics: Male; Humans; Adult; Female; Philadelphia Chromosome; Vincristine; Methotrexate; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 36279879
DOI: 10.1016/S2352-3026(22)00285-X -
Current Hematologic Malignancy Reports Jun 2017Most drugs used in standard regimens for acute lymphoblastic leukemia (ALL) were developed more than 30 years ago. Since that time, several new drugs have been... (Review)
Review
Most drugs used in standard regimens for acute lymphoblastic leukemia (ALL) were developed more than 30 years ago. Since that time, several new drugs have been developed and incorporated into ALL treatment. In spite of this, novel therapeutic approaches are still needed to improve outcomes for high-risk or relapsed ALL. This manuscript discusses newer treatment strategies, including purine nucleoside analogs, monoclonal antibodies, antibody drug conjugates, mammalian target of rapamycin (mTOR) inhibitors, proteasome inhibitors, histone deacetylase (HDAC) inhibitors, hypomethylating agents, spleen tyrosine kinase inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, Janus kinase-signal transducer and activator of transcription (JAK-STAT) inhibitors, anti-programmed cell death protein (anti-PD-1) antibodies, mitogen-activated protein kinase (MEK) inhibitors, CXCR4 antagonists, poly (ADP-ribose) polymerase (PARP) inhibitors, and FMS-like tyrosine kinase 3 (FLT3) inhibitors. Additionally, this manuscript discusses the impact of diagnostic approaches on management of ALL. Specifically, minimal residual disease is increasingly felt to be important and will likely dramatically impact the care of ALL patients in the near future.
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Clinical Trials as Topic; Epigenesis, Genetic; Histone Deacetylase Inhibitors; Humans; Immunoconjugates; Molecular Targeted Therapy; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proteasome Inhibitors; Protein Kinase Inhibitors; Signal Transduction; Treatment Outcome
PubMed: 28353016
DOI: 10.1007/s11899-017-0380-3 -
Neurosurgical Review Oct 2017We conducted a comprehensive review of the literature to characterize the etiology of secondary glioma following acute lymphocytic leukemia (ALL) patients. The analysis... (Review)
Review
We conducted a comprehensive review of the literature to characterize the etiology of secondary glioma following acute lymphocytic leukemia (ALL) patients. The analysis included 98 cases with an average age of onset of ALL of 5.9 years (range 1.5 to 26). The average latency period was 7.8 years until diagnosis of secondary glioma. Radiation therapy was administered in 92 cases for the primary malignancy at an average dose of 20.7 Gy. The median survival time of patients treated with multimodality treatment for secondary glioma was 23 months (95 % confidence interval 12-27 months), and multimodality therapy improved survival time significantly (p = 0.0029). The exact cause for the development of glioma following ALL is not clear. The risk of a secondary glioma in childhood cancer survivors may be influenced by genetic and other predisposing factors as well as by treatment type. In patients diagnosed with ALL, the risk of secondary glioma warrants a longer follow-up period that continues long after the risk of relapse of the primary malignancy has passed. Moreover, multimodality therapy should be considered in cases of secondary glioma following ALL.
Topics: Adolescent; Adult; Brain Neoplasms; Child; Child, Preschool; Combined Modality Therapy; Female; Glioma; Humans; Infant; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Young Adult
PubMed: 27159974
DOI: 10.1007/s10143-016-0733-8 -
International Braz J Urol : Official... 2022
Topics: Child; Humans; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Testicular Neoplasms
PubMed: 36037260
DOI: 10.1590/S1677-5538.IBJU.2022.0318 -
Expert Opinion on Biological Therapy Nov 2018Cellular immunotherapy with autologous or allogeneic T cells, genetically engineered to express chimeric antigen receptors (CARs) or T-cell receptors, in order to... (Review)
Review
Cellular immunotherapy with autologous or allogeneic T cells, genetically engineered to express chimeric antigen receptors (CARs) or T-cell receptors, in order to redirect their cytotoxic specificity toward malignant cells, is emerging as a promising new treatment modality. The most advanced approach in clinical development is the use of anti-CD19 CAR T-cells for the treatment of CD19 B-cell malignancies, including acute lymphocytic leukemia (ALL). Areas covered: Recently, the Food and Drug Administration (FDA) approved the first anti-CD19 CAR T-cell product, tisagenlecleucel, for the treatment of pediatric and young adult patients with relapsed/refractory ALL. In this overview, we described the advances in the field, including a summary of clinical trials with tisagenlecleucel in ALL published to date. Expert opinion: CAR T-cell therapy has been developed in the context of small clinical studies and very few centers have had to deal with the challenges of managing CAR T-cells administration. However, this approach is likely to become a standard option for patients with relapsed/refractory B-cell lineage ALL.
Topics: Adult; Antigens, CD19; Child; Humans; Immunotherapy; Immunotherapy, Adoptive; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Antigen, T-Cell; Young Adult
PubMed: 30296188
DOI: 10.1080/14712598.2018.1533951 -
Current Treatment Options in Oncology Mar 2017Opinion statementOver the past 15 years, the landscape of Ph+ ALL has changed dramatically. No longer the most dreaded form of acute leukemia, the advent of tyrosine... (Review)
Review
Opinion statementOver the past 15 years, the landscape of Ph+ ALL has changed dramatically. No longer the most dreaded form of acute leukemia, the advent of tyrosine kinase inhibitors (TKIs) has ushered in a new era, as TKIs have become the backbone of any treatment regimen for Ph+ ALL. A greater number achieve a complete remission allowing for more patients to get the transplant, although probably less patients need a transplant. For the first time in decades, there is hope for older patients with Ph+ ALL. Defining residual disease at an increasingly lower level of disease burdens termed minimal residual disease (MRD) has allowed treatment algorithms to be designed based on deep molecular responses. The aggregate of recent data suggest that this is the most important endpoint to predict for long-term outcome and to decide on the optimal post-remission approach, including transplant. Novel agents, such as blinatumumab, are likely to be incorporated into therapy for relapse and as initial therapy in an attempt to increase the number of patients who may have deep molecular responses. Many more patients with Ph+ ALL are long-term survivors, and the future is looking brighter for this group of patients.
Topics: Age Factors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Drug Discovery; Hematopoietic Stem Cell Transplantation; Humans; Neoplasm, Residual; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Treatment Outcome
PubMed: 28382538
DOI: 10.1007/s11864-017-0455-3 -
Human Antibodies 2022Acute lymphocytic leukemia (ALL) is a type of blood cancer that is more prevalent in children. Several treatment methods are available for ALL, including chemotherapy,... (Review)
Review
BACKGROUND
Acute lymphocytic leukemia (ALL) is a type of blood cancer that is more prevalent in children. Several treatment methods are available for ALL, including chemotherapy, upfront treatment regimens, and pediatric-inspired regimens for adults. Monoclonal antibodies (Mabs) are the novel Food and Drug Administration (FDA) approved remedies for the relapsed/refractory (R/R) adult ALL. In this article, we aimed to review studies that investigated the efficacy and safety of Mabs on ALL.
METHODS
We gathered studies through a complete search with all proper related keywords in ISI Web of Science, SID, Scopus, Google Scholar, Science Direct, and PubMed for English language publications up to 2020.
RESULTS
The most commonly studied Mabs for ALL therapies are CD-19, CD-20, CD-22, and CD-52. The best results have been reported in the administration of blinatumomab, rituximab, ofatumumab, and inotuzumab with acceptable low side effects.
CONCLUSION
Appling personalized approach for achieving higher efficacy is one of the most important aspects of treatment. Moreover, we recommend that the wide use of these Mabs depends on designing further cost-effectiveness trials in this field.
Topics: Adult; Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Agents, Immunological; Child; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Rituximab
PubMed: 35662114
DOI: 10.3233/HAB-211511 -
The Journal of International Medical... Mar 2021This report describes a patient who had acute lymphocytic leukemia with exudative retinal detachment (RD), which mimicked Vogt-Koyanagi-Harada disease (VKH). A... (Review)
Review
This report describes a patient who had acute lymphocytic leukemia with exudative retinal detachment (RD), which mimicked Vogt-Koyanagi-Harada disease (VKH). A 61-year-old woman presented with painless loss of vision in the left eye. Fundus examination revealed RD in her left eye. B-scan ultrasonography confirmed localized RD and choroidal thickening. Fundus fluorescein angiography revealed stippled pinpoint hyperfluorescence in the upper macula. One week later, reduced visual acuity was noted in the right eye. B-scan ultrasonography and optical coherence tomography revealed serous RD in both eyes. A provisional diagnosis of VKH was made. However, subsequent hematologic analysis detected an extremely high leukocyte count. Elevated numbers of leukocytes and tumor cells were found in cerebrospinal fluid. Bone marrow biopsy revealed 77% primary atypical blood cells, 89% of which were immature lymphocytes. The patient was subsequently diagnosed with acute lymphocytic leukemia and transferred to the Department of Hematology. However, the patient and her family refused chemotherapy; she eventually died. Our findings suggest that exudative RD, similar to VKH, could be a sign of leukemia. Pinpoint hyperfluorescence leakage is important for differential diagnosis, particularly with respect to VKH.
Topics: Female; Fluorescein Angiography; Humans; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retinal Detachment; Tomography, Optical Coherence; Uveomeningoencephalitic Syndrome
PubMed: 33765851
DOI: 10.1177/0300060520964373 -
Expert Opinion on Pharmacotherapy Dec 2016Advances in acute lymphocytic leukemia (ALL) therapy has led to long-term survival rates in children. However, only 30%-40% of adults achieve long-term disease-free... (Review)
Review
Advances in acute lymphocytic leukemia (ALL) therapy has led to long-term survival rates in children. However, only 30%-40% of adults achieve long-term disease-free survival. After relapse, the outcome of salvage chemotherapy is very disappointing with less than 10% of long survival. Novel agents are therefore desperately required to improve response rates and survival, but also the quality of life of patients. Areas covered: The following review is a comprehensive summary of various novel options reported over the past few years in the therapeutic area of adult ALL. Expert opinion: Identifying key components involved in disease pathogenesis may lead to new approaches. In a near future, the incorporation of monoclonal antibodies and T-cell directed approaches including blinatumomab and chimeric antigen receptor T cells may increase the cure rates and may reduce the need for intensive therapy.
Topics: Adenine Nucleotides; Adult; Antibodies, Monoclonal; Antineoplastic Agents; Arabinonucleosides; Clofarabine; Disease-Free Survival; Drug Discovery; Humans; Molecular Targeted Therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purine Nucleosides; Pyrimidinones; Quality of Life; Recurrence; Salvage Therapy
PubMed: 27759440
DOI: 10.1080/14656566.2016.1250884 -
Seminars in Hematology Jan 2009The term epigenetics refers to the study of a number of biochemical modifications of chromatin that have an impact on gene expression regulation. Aberrant epigenetic... (Review)
Review
The term epigenetics refers to the study of a number of biochemical modifications of chromatin that have an impact on gene expression regulation. Aberrant epigenetic lesions, in particular DNA methylation of promoter associated CpG islands, are common in acute lymphocytic leukemia (ALL). Recent data from multiple laboratories indicate that several hundred genes, involving dozens of critical molecular pathways, are epigenetically suppressed in ALL. Because these lesions are potentially reversible, the reactivation of these pathways using, for instance, hypomethylating agents may have therapeutic potential in this disease. Furthermore, the analysis of epigenetic alterations in ALL may allow: (1) identification of subsets of patients with poor prognosis when treated with conventional therapy; (2) development of new techniques to evaluate minimal residual disease; (3) better understanding of the differences between pediatric and adult ALL; and (4) new therapeutic interventions by incorporating agents with hypomethylating activity to conventional chemotherapeutic programs. In this review, we describe the role of epigenetic alterations in ALL from a translational perspective.
Topics: Adult; Age Factors; Child; Child, Preschool; DNA Methylation; Epigenesis, Genetic; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis
PubMed: 19100365
DOI: 10.1053/j.seminhematol.2008.09.008